Restless Legs Syndrome (RLS) is a well defined, recognised clinical entity characterised by unpleasant creeping, burning or pulling sensations deep in the legs, between the knees and the ankles and less frequently in the arms. The symptoms are present when the limbs are at rest, particularly in the evening and at night, and are generally relieved by movement. The consequence is the appearance of sleep disturbances, prolonged sleep latency, decreased total sleep time with reduced or absent slow wave sleep and decreased sleep efficiency.
Epidemiological studies have found RLS to be common with lifetime prevalence figures in adults ranging from 9% to 15% of the general population (Phillips B Epidemiology of restless legs syndrome in adults Archives of Internal Medicine 160 (14) 2137-2141 2000). The international RLS Study Group Criteria (1995) defines RLS patients as presenting the following symptoms (Walters A S Toward a better definition of the Restless Legs Syndrome Movement Disorders 10 (5) 634-642 1995):    1. A desire to move the limbs associated with paresthesias or dysesthesias.    2. Motor restlessness (during wakefulness patients move the limbs in attempt to relieve the discomfort).    3. Symptoms worse or exclusively present at rest with at least partial and temporary relief by activity.    4. Symptoms worsen in the evening or at night.
Other common features are sleep disturbances, periodic limb movements in sleep (PLMS) and similar involuntary movement while awake (Walters A S Toward a better definition of the Restless Legs Syndrome Movement Disorders 10 (5) 634-642 1995).
The number of PLM and related parameters are considered to be a marker for the severity of RLS since PLM are frequently associated with nocturnal arousals or awakenings.
Because of problems during sleep and wakefulness, people with RLS may have difficulties with their job, social life and recreational activities.
The pathogenesis of RLS remains unknown, but current evidence favours a disinhibition of normal central nervous system pacemakers, probably governed by multiple influences. Positron emission tomographic (PET) studies in RLS have supported the role of the dopaminergic system in the pathogenesis of the disorder. Turjanski et al disclose that both caudate and putamen 18F-dopa uptake were mildly reduced in RLS patients compared with control subjects, and this reached significance (p=0.04) in the putamen. The same study demonstrated a significant reduction in D2 dopamine receptor binding in the putamen in these patients (Turjanski N Neurology 52 932-937 1999). Similarly, Ruottinen et al. studied a group of drug-naïve RLS patients and demonstrated an 11% decrease in 18F-dopa uptake in the putamen and 12% in the caudate nucleus (Ruottinen H M Neurology 54 502-504 2000). These data are suggestive of a mild striatal presynaptic dopaminergic dysfunction.
No agents are currently indicated for the treatment of RLS in the U.S., although Restex®, a preparation of L-dopa has recently been launched in Germany. The other products used to treat RLS symptoms include opiates, benzodiazepines and some anticonvulsants. Dopamine agonists, such as cabergoline, pramipexole and ropinirole, have been also proposed for RLS treatment. All these treatments have disadvantages such as side effects, interactions, short duration of action and abuse potential. The available evidence suggests that a deficit of dopaminergic system plays an important role in RLS. Since MAOB inhibitors affect the metabolism of dopamine leading to a prolongation of the time course of dopamine on its receptor, we propose the use of α-amino derivatives in the treatment of RLS. Other disorders, where a deficit in the dopaminergic system plays an important role, are the addictive disorders that can be defined as pathological behaviour characterized by compulsive drug seeking and intake. Continued drug use is believed to cause protracted functional changes in the neural circuits involved in motivation that can lead to dependence, drug craving and relapse.
Typically different drugs of abuse (amphetamine, cocaine, heroine, nicotine, alcohol) even with different primary molecular target have the common action of increasing dopamine transmission in the mesolimbic system. Different approaches have been used in the treatment of addiction disorders and most of them aim to modulate the dopaminergic system.
MAOB inhibitors affect the metabolism of dopamine in human and primates leading to a prolongation of the time course of dopamine on its receptors. The use of MAOB inhibitor has been shown to be beneficial in the treatment of pathologies where a dopaminergic deficit is present like in PD.
New evidences support the hypothesis that MAOB inhibitors can be beneficial in the treatment of addictive disorders. Studies performed in rats and in human have shown that selegiline (a specific MAOB inhibitor) has a moderate anti-reinforcing effect during cocaine detoxification and may improve dopamine deficits during withdrawal which are thought to contribute to relapse events (Schiffer et al, 2003 Synapse 48:35-8).
Recently it has been observed that smokers have a reduced MAOB activity in platelet and brain. It has been hypothesized that reduced MAOB activity in the brain is involved in increasing the addictive properties of nicotine. In a multicenter phase II study lazabemide, another MAOB inhibitor (200 mg/day), seems to increase the percentage of smoking cessation (from 17 to 30%) (Berlin et al, 2002 Addiction 97:1347-1354).
Moreover it has been shown that also Na channel blockers can be effective in the treatment of addictive disorders. Indeed a recent clinical study has shown that topiramate (a Na channel blocker) is efficacious in the treatment of alcohol dependence (Johnson et al, 2003, The Lancet 361: 1677-1685).
Current treatments of addictive disorders include antidepressants drugs, opiate receptor agonists like methadone, opiate receptor antagonists and partial agonists like naltrexone and buprenorphine, benzodiazepines and disulfiram for alcohol detoxification. Disadvantages of these treatments include several side effects and still an unsatisfactory therapeutic efficacy.
Since there are evidences that compounds with MAOB inhibition activity and compounds with Na channel blockers activity can be effective in the treatment of addictive disorders we propose the use of α-amino derivatives, a chemical class of monoamine oxidase B (MAOB) inhibitors and sodium channel blockers of this invention in the treatment of addictive disorders.
WO90/14334, WO94/22808, WO97/05102, WO 97/0511 and WO 99/35215, the texts of which are incorporated by reference herein, disclose substituted benzylaminopropionamide compounds active on the central nervous system and useful as anti-epileptic, anti-Parkinson, neuroprotective, antidepressant, and antispastic hypnotic agents (see also Pevarello P. et al. (1998), J. Med. Chemistry, 41: 579-590). WO99/35125 and WO99/35123 disclose substituted benzylaminopropanamide compounds active on the central nervous system and useful as analgesic agents.